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PubMed2005

Towards replacing closed with open target selection strategies.

Increasingly, microbial production processes are being improved by targeted approaches. In directed strain improvement, the selection of the relevant targets is the limiting step in metabolic engineering. Currently, the identification of leads is still a random process relying largely on expert knowledge. Recently, this approach has been complemented by metabolic flux and control analysis approaches. However, both are closed approaches, and biological processes or interactions that are not currently known to exist, or to be important for bioproduct formation, are not taken into account. By contrast, the recently introduced functional genomics technologies enable an open approach towards target selection. In the near future, we might see that metabolomics, and its integration with transcriptomics and/or proteomics into a systems biology approach, in combination with multivariate data analysis tools, will become of increasing importance for the unbiased selection and ranking of targets, not only for strain improvement but also for bioprocess improvement.

Bacteria↗
PubMed2006

Systemic co-administration of depsipeptide selectively targets transfection enhancement to specific tissues and cell types.

Depsipeptide, a histone deacetylase (HDAC) inhibitor, kills tumor cells much more effectively than normal cells, and can produce significant antitumor activity in human cancer patients. Depsipeptide also increases the expression of lipoplex-delivered genes in cultured tumor cells, as well as following direct intra-tumoral injection. We now show that co-intravenous (i.v.) injection of depsipeptide with polyethylenimine (PEI):DNA complexes significantly increases the expression of PEI-delivered genes in normal, as well as in tumor-bearing mice. At the tissue level, depsipeptide-mediated enhancement of gene expression was selectively targeted to the lung, liver and spleen. At the cellular level, depsipeptide significantly increased the expression of the i.v., PEI co-delivered wild-type human p53 gene in metastatic breast cancer cells, but not in adjacent normal cells. Thus, the ability of depsipeptide to enhance the expression of systemically delivered genes is selectively targeted at both the tissue and cellular levels, without requiring the use of ligand- or promoter-based approaches. Analyzing HDAC-based targeting of gene expression may identify host genes that control the expression of systemically delivered genes.

Animals↗
PubMed1999

Separate signals for target selection and movement specification in the superior colliculus.

At any given instant, multiple potential targets for saccades are present in the visual world, implying that a "selection process" within the brain determines the target of the next eye movement. Some superior colliculus (SC) neurons begin discharging seconds before saccade initiation, suggesting involvement in target selection or, alternatively, in postselectional saccade preparation. SC neurons were recorded in monkeys who selected saccade targets on the basis of motion direction in a visual display. Some neurons carried a direction-selective visual signal, consistent with a role in target selection in this task, whereas other SC neurons appeared to be more involved in postselection specification of saccade parameters.

Animals↗
PubMed2003

Yeast sphingolipid bypass mutants as indicators of antifungal agents selectively targeting sphingolipid synthesis.

Standard methods for evaluating the target specificity of antimicrobial agents often involve the use of microorganisms with altered expression of selected targets and thus either more resistant or more susceptible to target specific inhibitors. In this study we present an alternative approach that utilizes physiological bypass mutants. The Saccharomyces cerevisiae sphingolipid bypass mutant strain AGD is able to grow without making sphingolipids and importantly, tolerates loss-of-function mutations in the otherwise essential genes for both serine palmitoyltransferase (SPT) and inositol phosphorylceramide (IPC) synthase. We found that strain AGD was >1000-fold more resistant than the wild-type strain to selective inhibitors of SPT and IPC synthase. In contrast, strain AGD, which due to abnormal composition of the plasma membrane is sensitive to a variety of environmental stresses, was more susceptible than the wild-type to amphotericin B, voriconazole, and to cycloheximide. We show that in a simple growth assay the AGD strain is an appropriate and useful indicator for inhibitors of IPC synthase, a selective antifungal target.

Acyltransferases↗
PubMed2002

Considerations in target selection in apraxia of speech treatment.

This article presents a three-step decision process to determine the targets for treatment of speakers with apraxia of speech: (1) identification of which aspect of speech motor control (articulation or prosody) to address, (2) definition of specific targets within each category, and (3) embedding the target in larger units for practice. Phonetic and linguistic parameters that influence target selection are identified. Recently published treatment reports are examined for both the selection system used and the actual targets chosen. New considerations regarding how to choose treatment targets are discussed.

Apraxias↗
PubMed2001

The effect of target-selection strategy on phonological learning.

In this study, 48 children with moderate or severe delays in phonological ability received treatment for four phonemes, selected in accordance with either traditional or nontraditional target-selection criteria. Children who received treatment for phonemes that are early developing and associated with greater productive phonological knowledge showed greater progress toward acquisition of the target sounds than did children who received treatment for late-developing phonemes that were associated with little or no productive phonological knowledge. Between-group differences in generalization learning were not observed. Child enjoyment of therapy did not differ between groups, but parental satisfaction with treatment progress was greater for children in the traditional group than for children in the nontraditional group.

Articulation Disorders↗
PubMed1999

TARPARE: a method for selecting target audiences for public health interventions.

OBJECTIVE: This paper presents a model to assist the health promotion practitioner systematically compare and select what might be appropriate target groups when there are a number of segments competing for attention and resources. METHOD: TARPARE assesses previously identified segments on the following criteria: T: The Total number of persons in the segment; AR: The proportion of At Risk persons in the segment; P: The Persuability of the target audience; A: The Accessibility of the target audience; R: Resources required to meet the needs of the target audience; and E: Equity, social justice considerations. The assessment can be applied qualitatively or can be applied such that scores can be assigned to each segment. Two examples are presented. CONCLUSIONS: TARPARE is a useful and flexible model for understanding the various segments in a population of interest and for assessing the potential viability of interventions directed at each segment. The model is particularly useful when there is a need to prioritise segments in terms of available budgets. IMPLICATIONS: The model provides a disciplined approach to target selection and forces consideration of what weights should be applied to the different criteria, and how these might vary for different issues or for different objectives. TARPARE also assesses segments in terms of an overall likelihood of optimal impact for each segment. Targeting high scoring segments is likely to lead to greater program success than targeting low scoring segments.

Health Promotion↗
PubMed1996

Morphologic and neurochemical target selectivity of regenerating adult photoreceptors in vitro.

Regenerating adult central nervous system (CNS) neurons must re-establish synaptic circuits in an environment very different from that present during development. However, the complexity of CNS circuitry has made it extremely difficult to assess the selectivity and mechanisms of synaptic regeneration at the cellular level in vivo. The synaptic preferences of adult photoreceptors were examined by using a defined cell culture system known to support regenerative process growth, presynaptic varicosity formation, and establishment of functional synapses. Immunolabeling for synaptic vesicle protein 2 and ultrastructural analysis demonstrated that cell-cell contacts made by photoreceptors were synaptic in nature. Target selectivity was determined by quantitative analysis of contacts onto normal and novel target cell types in cultures in which opportunities to contact all retinal cell types were present. Target cells were identified by morphology and immunolabeling for the amino acid neurotransmitters glutamate, aspartate, gamma-aminobutyric acid (GABA), and glycine. Regenerating photoreceptors showed a strong preference for novel multipolar cell targets (amacrine and ganglion cells) over normal photoreceptor, horizontal, and bipolar cell targets. Additionally, photoreceptors were selective for targets containing the transmitter GABA. These results indicate first, that the normal synaptic partners for photoreceptors are not intrinsically the optimal targets for regenerative synapse formation, and second, that GABA may modulate synaptic targeting by adult photoreceptors.

Ambystoma↗
PubMed2004

Target selectivity in EF-hand calcium binding proteins.

EF-hand calcium binding proteins have remarkable sequence homology and structural similarity, yet their response to binding of calcium is diverse and they function in a wide range of biological processes. Knowledge of the fine-tuning of EF-hand protein sequences to optimize specific biochemical properties has been significantly advanced over the past 10 years by determination of atomic resolution structures. These data lay the foundation for addressing how functional selectivity is generated from a generic ionic signal. This review presents current ideas about the structural mechanisms that provide the selectivity of different EF-hand proteins for specific cellular targets, using S100 and calmodulin family proteins to demonstrate the critical concepts. Three factors contribute significantly to target selectivity: molecular architecture, response to binding of Ca(2+) ions, and the characteristics of target binding surfaces. Comparisons of calmodulin and S100 proteins provide insights into the role these factors play in facilitating the variety of binding configurations necessary for recognizing a diverse set of targets.

Amino Acid Sequence↗
PubMedDate not supplied

Selective targeting of the retinal pigment epithelium using an acousto-optic laser scanner.

Selective targeting of the retinal pigment epithelium (RPE) is a new strategy for treating certain retinal disorders while preserving adjacent photoreceptors. The treatment currently relies on a complex laser system to produce the required microsecond pulse structure. In our new approach, we scan the focus of a continuous-wave (cw) laser beam with acousto-optic deflectors to produce microsecond-long exposures at each RPE cell. Experiments were performed in vitro with a bench-top scanner on samples of young bovine RPE and in vivo on Dutch belted rabbits with a slit-lamp adapted scanner. Effective dose 50% (ED50) for RPE damage was determined in vitro by fluorescence cell viability assay and in vivo by fluorescein angiography. Damage to individual RPE cells was achieved with laser power on the order of 100 mW. Using separated scan lines, we demonstrate selectivity in the form of alternating lines of dead and surviving cells that resemble the scan pattern. Selectivity is also shown by the absence of retinal thermal coagulation in vivo. Selective RPE damage is feasible by rapidly scanning a cw laser beam. The scanning device is an attractive alternative to conventional laser coagulation and pulsed laser targeting of the RPE.

Acoustics↗
PubMed2002

A method for prediction of accessible sites on an mRNA sequence for target selection of hammerhead ribozymes.

Hammerhead ribozymes are short RNA molecules endowed with endoribonucleolytic activity. Their use as molecular tools for specific inhibition of gene translation is affected by many factors including the target accessibility. A method for the prediction of accessible target sites for hammerhead ribozymes within a given RNA sequence is described. This method maps all putative NUH cleavage sites (N = A, C, G, U and H = A, C, U) and picks out short flanking regions as the binding domain for the corresponding ribozyme. The probabilistic level of unfolding, accessibility score (AS), is then calculated for each target region on the basis of a comparison of all folding structures obtained for the target RNA and arranged according to the Boltzmann's distribution. At the end, a series of imposed limits gives the best target sequences endowed with highly probable accessibility and with a potentially active catalytic structure of the hammerhead sequence. A successive experimental approach to verify the effective accessibility of selected targets was used. For that, antisense oligonucleotides addressed to the coding region of bcl2 mRNA were synthesized and administered to the MCF7 human cell line. The inhibition of gene expression, as measured by western analysis of the BCL2 protein, demonstrated that all target sites selected on the basis of their putative accessibility were actually sensitive to antisense treatments while the inaccessible ones were not. The application of this target discovery method to ribozyme design is proposed in order to satisfy a crucial condition.

Algorithms↗
PubMed2002

Selective targeting and inducible destruction of human cancer cells by retroviruses with envelope proteins bearing short peptide ligands.

In the accompanying study, we show how retroviral tropism can be redirected by insertion of short peptide ligands at multiple locations in envelope. Here we use this approach to selectively target and destroy human cancer cells. Many cancer cells overexpress specific cell surface receptors. We have generated Moloney murine leukemia virus (MLV) envelope derivatives bearing short peptide ligands for gastrin-releasing protein (GRP) and human epidermal growth factor receptors. Pseudotyped viruses containing these chimeric envelope derivatives selectively transduce human cancer cell lines that overexpress the cognate receptor. A retrovirus targeting the GRP receptor can deliver the thymidine kinase gene to human melanoma and breast cancer cells, which are killed by the subsequent addition of ganciclovir. Collectively, our results demonstrate that short peptide ligands inserted at appropriate locations in MLV envelope can selectively target retroviruses to human cancer cells and deliver a therapeutically relevant gene.

Amino Acid Sequence↗
PubMed1998

Activity-dependent cortical target selection by thalamic axons.

Connections in the developing nervous system are thought to be formed initially by an activity-independent process of axon pathfinding and target selection and subsequently refined by neural activity. Blockade of sodium action potentials by intracranial infusion of tetrodotoxin in cats during the early period when axons from the lateral geniculate nucleus (LGN) were in the process of selecting visual cortex as their target altered the pattern and precision of this thalamocortical projection. The majority of LGN neurons, rather than projecting to visual cortex, elaborated a significant projection within the subplate of cortical areas normally bypassed. Those axons that did project to their correct target were topographically disorganized. Thus, neural activity is required for initial targeting decisions made by thalamic axons as they traverse the subplate.

Action Potentials↗
PubMed1995

Attention and target selection for smooth pursuit eye movements.

Two rhesus monkeys were trained to track a small moving target in the presence of a moving distractor. The target and distractor were distinguished by their color. Smooth pursuit eye movements were quantified in terms of the latency of the eye movement and the open-loop eye acceleration profile. Smooth pursuit latencies for single targets were on the order of 100 msec. When the target was paired with a distractor moving in the same direction as the target, pursuit latencies decreased to roughly 85 msec. When the target was paired with a distractor moving in the opposite direction, pursuit latencies increased to roughly 150 msec. The motion of the distractor had no significant effect on the eye acceleration profile. Experiments were performed to dissociate visual search for the target from pursuit initiation by providing a spatial cue rather than the color cue. These experiments showed that visual search necessarily preceded pursuit initiation only when the distractor moved in the opposite direction relative to the target. In this case, visual search contributed about 25 msec to the overall latency of pursuit. Control experiments showed that the monkey need not attend to the distractor in order for it to influence the latency of pursuit. A network model was developed in which units that represent the motions of the target and distractor compete against one another. Attention serves to bias the outcome of this competition toward the direction of the selected target. The performance of this network exhibits a striking parallel to the effect of the distractor on smooth pursuit latency.

Animals↗
PubMed2005

Comparison of functional MR imaging guidance to electrical cortical mapping for targeting selective motor cortex areas in neuropathic pain: a study based on intraoperative stereotactic navigation.

PURPOSE: To assess the concordance between data from functional MR imaging (fMRI) guidance and the intraoperative electrical cortical mapping (iCM) in targeting selective motor cortex areas in refractory neuropathic pain. METHODS: Twenty-one patients (11 women and 10 men; mean age, 55.6 years) with refractory central (ischemic, 8 cases) and neuropathic pain (trigeminal neuropathy, 6 cases; syrinx/amputation/plexus trauma, 7 cases) underwent surgery for the implantation of an epidural electrode for chronic motor cortex stimulation (MCS) with general anesthesia and a frameless neuronavigation system used for the image-guided targeting procedure. All patients were studied by preoperative fMRI and epidural iCM with somatosensory evoked potentials and motor cortex stimulodetection. fMRI investigated systematically motor tasks of both hands and that related to the somatic area (foot or tongue) affected by pain. fMRI data were analyzed with the Statistical Parametric Mapping99 software (initial analysis threshold [AT] corresponding to P < .001), registered in the neuronavigation system and correlated intraoperatively with iCM. Matching of fMRI and iCM was specifically examined, focusing the study on hand mapping. RESULTS: Concordance between contours of fMRI activation area and iCM in precentral gyrus (mean distance, 3.8 mm) was found in 20/21 patients (95%). Because precision of iCM was suboptimal in 7 patients, concordance for more restrictive values of the AT (P < .0001) was found in only 13 of these 20 patients. Concordance was not found in one patient, as result of image distortion and residual motion artifact. CONCLUSIONS: In this study, fMRI guidance provides information that matches those of an independent functional method. These data illustrate the functional accuracy of fMRI guidance for the operative targeting of selective motor cortex areas in neuropathic pain.

Adult↗
PubMed2005

Polysialylated neural cell adhesion molecule is necessary for selective targeting of regenerating motor neurons.

It is well established that peripheral nerves regenerate after injury. Therefore, incomplete functional recovery usually results from misguided axons rather than a lack of regeneration per se. Despite this knowledge very little is known about the molecular mechanisms regulating axon guidance during regeneration. In the developing neuromuscular system the neural cell adhesion molecule (NCAM) and its polysialic acid (PSA) moiety are essential for proper motor axon guidance. In this study we used a well established model of nerve transection and repair to examine whether NCAM and/or PSA promotes selective regeneration of femoral motor nerves in wild-type and NCAM (-/-) mice. We found that regenerating axons innervating the muscle pathway and, to a lesser extent, cutaneous axons in the sensory pathway reexpress high levels of PSA during the time when the cut axons are crossing the lesion site. Second, we found that motor neurons in wild-type mice preferentially reinnervated muscle pathways, whereas motor neurons in NCAM (-/-) mice reinnervated muscle and cutaneous pathways with equal preference. Preferential regeneration was not observed in wild-type mice when PSA was removed enzymatically from the regenerating nerve, indicating that this form of selective motor axon targeting requires PSA. Finally, transgenic mice were used to show that the number of collateral sprouts, their field of arborization, and the withdrawal of misprojected axons were all attenuated significantly in mice lacking PSA. These results indicate that regenerating motor axons must express polysialylated NCAM, which reduces axon-axon adhesion and enables motor neurons to reinnervate their appropriate muscle targets selectively.

Animals↗
PubMed1997

Evidence for selective target processing with a low perceptual load flankers task.

In this article, we demonstrate that selective target processing is possible when the perceptual load of the task is low. We presented a row of three items with two different identities: one identity for the target letter and one for the two flankers (B. A. Eriksen & C. W. Eriksen, 1974). Such stimulus arrays have been defined as low-load displays (Lavie & Tsal, 1994). We investigated whether subjects could ignore the irrelevant flankers, which were never response alternatives, by manipulating the predictive relationship between the flankers and the response (Miller, 1987). In a high-correlation block, the identity of the flankers was highly predictive of the target identity, whereas in a low-correlation block, the predictive value of the flankers was reduced. We varied (1) whether or not the target location was precued, (2) the flanker's category (digit vs. letter), (3) the target-flanker proximity (near = .3 degree vs. far = 5 degrees), and (4) the size of the characters. The results indicate that subjects were influenced by the predictive value of near flankers and that the magnitude of this effect was jointly modulated by the target-flanker categorical overlap and by the size of the characters. In contrast, null flanker effects were obtained for far letter flankers in the precue condition, and for far digit flankers, regardless of attentional cuing. These findings (1) are inconsistent with suggestions (Lavie, 1995) that irrelevant stimuli automatically capture attention, and (2) support the notion that target-flanker distinctiveness plays a role when the perceptual load of the task is low.

Analysis of Variance↗